Design and Synthesis of the First Generation of Novel Potent, Selective, and in Vivo Active (Benzothiazol-2-yl)acetonitrile Inhibitors of the c-Jun N-Terminal Kinase

Abstract

Several lines of evidence support the hypothesis that c-Jun N-terminal kinase (JNKs) plays a critical role in a wide range of diseases including cell death (apoptosis)-related disorders (neurodegenerative diseases, brain, heart, and renal ischemia, epilepsy) and inflammatory disorders (multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases). Screening of our internal compound collection for inhibitors of JNK3 led to the identification of (benzothiazol-2-yl)acetonitrile derivatives as potent and selective JNK1, -2, -3 inhibitors. Starting from initial hit 1 (AS007149), the chemistry and initial structure-activity relationship (SAR) of this novel and unique kinase inhibitor template were explored. Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3. Therefore, compound 6 was further optimized by exploring a number of distal combinations in place of the chlorine atom. This led to the observation that the presence of an aromatic group, two carbons away from the aminopyrimidine moiety and bearing substituents conferring hydrogen bond acceptor (HBA) properties, could improve the potency. Further improvements to the biological and biopharmaceutical profile of the most promising compounds were performed, resulting in the discovery of compound 59 (AS601245). The in vitro and in vivo anti-inflammatory potential of this new JNK inhibitor was investigated and found to demonstrate efficacy per oral route in an experimental model of rheumatoid arthritis (RA).

Polychaete trunk neuroectoderm converges and extends by mediolateral cell intercalation

“…2 O-Q). We treated larvae between 48 and 58 hpf with two chemically distinct inhibitors of JNK, SP600125 (30) or AS601245 (31) and found that the active autophosphorylated form of JNK (30) was strongly reduced in larval extracts, as evidenced by immunodetection of the conserved diphosphorylated Thr-Pro-Tyr epitope of JNK ( Fig. 2 E and F) (32).…”

The contribution of c-Jun N-terminal kinase activation and subsequent Bcl-2 phosphorylation to apoptosis induction in human B-cells is dependent on the mode of action of specific stresses

“…To further support the role of JNK in vincristine-mediated phosphorylation of Bcl-2 we examined the effects of several other commercially available inhibitors, including a second, structurally different, JNK-inhibitor (JNK inhibitor V; Gaillard et al, 2005), and an inactive structural analogue of SP6 (JNK inhibitor II; Bennett et al, 2001) that served a negative control for SP6. Although SP6 is the most commonly used inhibitor of the pathway, both it and JNK inhibitor V are ATP-competitive inhibitors that show a high degree of specificity towards the JNK1, 2, and 3 isoforms compared to a variety of other kinases (Bennet et al, 2001, Gaillard et al, 2005.…”

“…Although SP6 is the most commonly used inhibitor of the pathway, both it and JNK inhibitor V are ATP-competitive inhibitors that show a high degree of specificity towards the JNK1, 2, and 3 isoforms compared to a variety of other kinases (Bennet et al, 2001, Gaillard et al, 2005. In addition, we also examined the effect of inhibitors of the ERK and p38 pathways (U0126 and SB2, respectively).…”

“…Both activated the JNK pathway in a sustained manner, as analyzed by phosphorylation of the JNK protein and induction of its downstream target c-Jun protein. However, two structurally unrelated JNK inhibitors, SP6 and JNK inhibitor V (Bennet et al, 2001, Gaillard et al, 2005 blocked apoptosis induced only by vincristine, not by arsenite. In contrast, an inactive structural analogue of SP6 had no effect, nor did inhibitors of ERK and p38 MAP kinase pathways commonly activated by cellular stress.…”

Neccessasity of Bio-imaging Hybrid Approaches Accelerating Drug Discovery Process (Mini-Review)

“…For lead optimization, techniques such as hit evaluation [7], (Bio)isosteric replacements [18] and hit fragmentation [44] could be used. However, these techniques are beyond the scope of this review and will not be discussed further.…”